Huntington's disease is a devastating, universally fatal, untreatable neurodegenerative disorder, which is debilitating and inflicts terrible suffering on the patient's mind and body. Human neural stem cells have been identified as a potential alternative cellular substrate for treatment, but to date, have not been tested for long- term therapeutic efficacy in disease relevant animal models (transgenic HD-mice). Our long-term goal is to assess the safety and temporal efficacy of hNSC transplantation in HD patients. The current objective is to determine if hNSC grafts are a potent long-lasting therapy that structurally protect neurons and reverse functional deficits associated with HD in transgenic mice. Our central hypothesis is that intrastriatal delivery of hNSC into previously "desensitized" transgenic HD mice will provide neuroprotection, improving measures in structural neuroanatomy, as well as reduce motor and cognitive deficits. The rationale for the proposed research is that once it is known if fetal hNSC grafts ameliorate progressive deficits in HD mice, we can pursue safety and tolerability studies in this most relevant animal model and subsequently employ a non-human primate model for HD as a logical next-step before clinical translation. Guided by preliminary data, this hypothesis will test the following two Specific Aims, that: 1) intrastriatal administration of hNSC will prevent HD pathology and behavioral deficits and 2) prolong the survival of HD transgenic mice. Utilizing a novel "desensitization" paradigm that allows grafted hNSC to bypass immunorejection, we will determine the effects of grafted hNSC on host anatomical structure and function and correlate these results to overall lifespan. In aim#1, immunohistochemical analysis and behavioral testing will be used to complement survival studies in Aim#2, in an effort to bridge a critical gap in knowledge for HD therapeutics. This research is innovative, as it 1) focuses on "desensitization" as a novel means to bypass graft rejection, 2) advances our knowledge of the functional efficacy of this approach by utilizing a true disease specific genetic model, and 3) will shed valuable insight for the future advancement of hNSC therapy in HD. This proposal is significant as rigorously testing hNSC therapies in transgenic mice more accurately depicts human HD, and therefore, the proposed experiments are more likely to provide quality translatable results to the clinic. The outcomes are expected to vertically advance the field of HD therapy through the blending of neurosurgery and stem cell biology. The knowledge obtained here has the potential to provide a therapeutic option that will reduce the terrible symptoms and prevent certain death associated with HD. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health and the NIH-NINDS's mission because the discovery of human stem cell based treatments that successfully slow or reverse progressive neurodegeneration and behavioral deficits will help develop a desperately needed treatment for HD patients. Furthermore, development of human stem cell therapies are needed now more than ever with the advent of exciting new technologies centered on patient-derived induced neural cells. Thus, the proposed research is relevant to the part of NIH's mission that pertains to the application of knowledge that enhances health and reduces the overall burden of illness.